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CAR-T cell therapy targeting MUC17 in gastric tumors
Sangwoo Park1,2,3, Cassidy E Ho1,3, Filippo Birocchi1,2,3
1Krantz Family Center for Cancer Research and Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
Background:
Chimeric antigen receptor (CAR)-T cell therapy has achieved significant success in hematologic malignancies; however, its efficacy in solid tumors remains limited. A major limitation is the difficulty in identifying suitable target antigens that are abundantly expressed on the surface of tumor cells while sparing life-sustaining normal tissues.
Methods:
We identified MUC17, a membrane-tethered mucin-type glycoprotein with minimal expression in normal tissues and frequent upregulation in gastric cancers, as a potential target for CAR-T therapy. We developed and validated MUC17-specific CAR-T cells incorporating a 4-1BB/CD3ζ signaling domain. In vitro assays assessed cytotoxicity, cytokine secretion, and T cell phenotypes across multiple gastric cancer cell lines, including CRISPR-mediated MUC17 knockout controls. In vivo efficacy was evaluated using NSG xenograft models.
Results:
MUC17 CAR-T cells exhibited potent, antigen-specific cytotoxicity, robust cytokine release, and sustained effector functions characterized by enrichment of central memory phenotypes. In vivo, MUC17 CAR-T cells significantly suppressed tumor growth without signs of toxicity in GSU and ASPC-1 models.
Conclusions:
These findings support MUC17 as a promising immunotherapeutic target for gastric cancer and demonstrate how targeting glycocalyx-associated antigens can expand the range of surface proteins amenable to CAR-T cell-based therapies in solid tumors.
Insights
Chimeric antigen receptor (CAR)-T cell therapy shows promise for gastric cancer by targeting the MUC17 antigen. MUC17-specific CAR-T cells effectively suppressed tumor growth in preclinical models with minimal toxicity.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- CAR-T cell therapy is effective in blood cancers but limited in solid tumors due to antigen identification challenges.
- Identifying tumor-specific antigens that spare normal tissues is crucial for solid tumor CAR-T efficacy.
Purpose of the Study:
- To evaluate MUC17 as a novel target antigen for CAR-T cell therapy in gastric cancer.
- To develop and validate MUC17-specific CAR-T cells for solid tumor treatment.
Main Methods:
- Identified MUC17 as a target antigen with low normal tissue expression and high gastric cancer upregulation.
- Developed MUC17-specific CAR-T cells with a 4-1BB/CD3ζ signaling domain.
- Assessed in vitro cytotoxicity, cytokine release, and T cell phenotypes; evaluated in vivo efficacy in NSG xenograft models.
Main Results:
- MUC17 CAR-T cells demonstrated potent, antigen-specific killing of gastric cancer cells.
- CAR-T cells exhibited robust cytokine secretion and sustained effector functions with a central memory phenotype.
- In vivo studies showed significant suppression of tumor growth in gastric cancer models without observed toxicity.
Conclusions:
- MUC17 is a promising immunotherapeutic target for gastric cancer.
- Targeting cell surface glycoproteins like MUC17 expands potential CAR-T targets in solid tumors.
- This approach enhances the applicability of CAR-T cell therapy for challenging solid malignancies.
